Immunological aspects of infections part 5

Most pathogenic microorganisms have evolved methods of resisting phagocytosis. For example, grup A streptococci have cell surface structures called M proteins of which there are now more than 120 antigenically distinct molecules that inhibit direct phagocytosis, mainly by preventing deposition of complement on the organism. Another example is the pneumococcal polysaccharide capsule of which there are thirty or forty distinct polysaccharides. Another  approach  (taken by both group A streptococci and staphylococci) is the release of potent extracellular toxins, which kill phagocytes with the formation of pus. An intriguing bacterium, mycobacterium tuberculosis, can be ingested by phagocytes but resists intracellular killing, often persisting for years in the macrophage.

Immunological aspects of infections part 4

The macrophages reside in the subepithelial tissues of the skin and intestine and line the alveoli of the lungs. Microbes that penetrate an epithelial surface will encounter local tissue macrophages called histocytes.  If organism enters via blood or lymph, then defense is provided by fixed macrophages called Kupffer cells, which line the sinusoids of the liver. Similar fixed macrophages called Langerhans cells are also present in the epidermis of the skin. Once engaged with the organism, these macrophages release a number of macrophage-derived cytokines, which nonspecifically amplify the immunological and inflammatory reactions to the invading microbe.

Immunological aspects of infections part 3

The polymorpholeukocytes are a large pool of phagocytic cells that are both circulatory and in the bone marrow. Invading organisms trigger an inflammatory cascade, which stimulates these cells to adhere to vascular epithelium and actively migrate toward the infection. Phagocytosis is promoted by opsonins (usually IgG antibody) and complement.

Immunological aspects of infections part 2

NONSPECIFIC RESISTANCE

Nonspecific or natural resistance refers to barriers, secretions, and normal flora that make up our external defenses. Phagocytes and complement are also involved. Mechanical barriers are highly effective, and the skin (our largest organ) is highly suited to this protection; loss of a major part of the skin (secondary to burns, acids, etc) immediately exposes the host to marked susceptibility to infection. The mucosal lining of mouth and respiratory tract is another excellent defense mechanism. Yet, a defect  in the mucosal lining of the respiratory tract, which occurs in cystic fibrosis, result in a hightened susceptibility to many infections. These are examples of a defect in the epithelium or epithelial lining. In general, however, it is the mobilization of the phagocytic cells such as monocytes/macrophages and polymorphonuclear leukocytes that ingest invading microorganisms and kill them.

Immunological aspects of infections part 1

From the moment of birth, the host is constantly exposed to a wide variety of bacteria and viruses. In general, the host manages to either eliminate or ward off these invading organisms, and a symbiosis is achieved between microbes and the host. How does this occur? There are two major pathways to achieve this resistance: nonspecific and adaptive

Basic components of the immune system part 164

Finally, a better understanding of the controls that act on T cells to stimulate or inhibit them has led to the use of reagents to enhance antitumor T-cell activity. For example, blocking antibodies to the inhibitory T-lymphocyte antigen CTLA-4, manipulation of regulatory T cells,  antibodies to PDL or its ligand PDLI, and enhancement of co-stimulating molecules like B7 on antigen-presenting cells are a few examples of reagents that are being used in this manner in conjunction with vacci-treatments.

Basic components of the immune system part 163

The importance of innate immunity and the emergence of the toll-like receptors have led to the recognition that immune modifiers must be an essential component of any cancer vaccine. The inclusion of QS21, ISCOMS, Montanide, heat shock proteins, CpG,BCG, and granulocyte-macrophage colony-stimulating factor with cancer vaccines reflect this. Of interest in this respect are the anecdotal  success of Coley's toxin at the turn of the nineteenth  century ( a heat-killed mixture of streptococcal cells probably superantigen broths), which may now be reinterpreted in the light of the newly identified immune response modifiers.

Basic components of the immune system part 162

The effort to create cancer vaccines using allogeneic cell lines, differentiation antigens (such as gp100 and MART1), cancer testes (CT) antigens (such as MAGE, NY-ESO-1) or other common molecules (such as carcinoembryonic antigen, mucins, prostate-specific antigen, and prostatic acid phosphatase) represent this approach. Within this approach lie several subthemes. Thus, CT antigens,  which are not expressed on normal somatic tissues but only on  cancers or gonads, might be a better target for breaking tolerance than are differentiation antigens expressed on somatic tissues. Another subtheme is the idea that artificially mutated differentiation or CT antigens as vaccines might be better at breaking tolerance than their wild-type counterparts. Finally, there is a multiplicity of choices of delivery agents for these antigens - whole proteins, peptides, RNA, DNA, viral vectors, DCs and so on.

Basic components of the immune system part 161

Cancer patients and healthy subjects often harbor a repertoire of self-reactive T cells and antibodies. This led to the idea that if one could break  immunological tolerance  to these self-antigens in a controllable manner one would find a "therapeuitic window" in which an autoimmune response might damage cancers more than normal tissues. This approach has worked reasonably well with chemotherapies, which, although not cancer specific, can confer clinical benefit  with acceptable morbidities.

Basic components of the immune system part 160

Jonuleit and colleagues directly compared within each of eight patients the immunogenicity of immature DCs (generated according to Nestle and colleagues in FCS-containing media using GM-CSF and IL-4) to mature DCs generated in the absence  of FCS and matured by a cocktail consisting of TNF-α, IL-1β, IL-6 and PGE2 mimicking the composition of monocyte conditioned medium. These two different DC populations were administered intranodally into opposite inguinal lymph nodes. FCS-free mature DCs induced stronger T-cell responses, both to the two recall antigens used (tetanus toxoid and PPD/tuberculin) and to tumor peptides. Interestingly, however, both immature and mature  DCs showed an expansion of peptide-specific T cells by tetramer staining; yet, only mature DCs induced IFN-γ-producing and lytic CD8 T cells. These findings suggest the interesting possibillity that the immature DCs might have induced regulatory T cells rather than effector T cells, an  observation previously noted in studies with normal volunteers

Basic components of the immune system part 159

Monocyte-derived Dendritic Cells (DCs) were the first to be used for treating melanome patients, and several pilot studies have been published. Most used defined antigens in the form of peptides, but in some studies, tumor lysates or autologous DC tumor hybrids were also employed.  The first trial, published  in 1998 by Nestle and colleagues, aroused great interest  given an overall response rate of 30% in stage IV patients (ie, distant metastases), including complete responses. An important point in the first study by Nestle and colleagues was that they use fetal calf serum (FCS) during DC generation, and  this might have contributed to the observed effects by providing nonspecific helper epitopes and by promoting the maturation of DCs.

Basic components of the immune system part 158

Focusing more closely on the type of DC (Dendritic cells) needed to achieve its vaccine potential, the subsets of DCs could prove critical. Much of the current research is being carried out with monocyte-derived DCs, which are potent and homogenous  stimulators of immunity. Monocyte-derived DCs can be readily generated within a few days in large numbers (300million-500million mature DCs per apheresis) from precursors in the blood without the need for pretreating in patients with various cytokines such as GM-CSF or FLT 3-L. Rather, one obtains population of immature DCs by exposing monocyte to GM-CSF and IL-4, and then they are differentiated into mature DCs by various stimuli  such as toll-like receptor (TLR) ligands (LPS or poly I:C), inflammatory cytokines (IL-1β, TNF-α, IL-6 and PGE2), or CD40L. The use of DCs that have received a maturation stimulus is likely to be important to induce strong immunity. It has become clear that antigen delivered on immature or incompletely mature d DCs can even induce tolerance. However, the type and the duration of the maturation stimulus remain to be determined and may influence efficacy. At this time, monocyte derived DCs are the most accessible and homogenous population of DCs.

Basic components of the immune system part 157

CELLULAR VACCINES  AND MODULATION THEREOF

DENDRITIC CELL VACCINES

Recently, much attention has focused on the area of dendritic cell vaccines in the treatment of cancers. The immunological basis of current approaches to therapeutic cancer vaccination (often called "vacci-treatment") has been established over the past decade or longer. These new developments are mainly based on the lessons learned from the clinical testing of these approaches. In particular, three lessons are  worthy of note:

• First, recent randomized phase III trials suggest that vacci-treatment with autologous DCs expressing prostatic acid phosphatase or with autologous tumor-derived heat shock protein (HSP gp96) peptide complexes are showing progress in cancer patient survivals.
• Second, immunological monitoring of many clinical trials has failed to identify a surrogate marker for clinical outcomes.
• Third, many articles and reviews  suggest that protective immunity to human cancer is elicited by the mutated antigenic repertoire unique to each cancer.

Basic components of the immune system part 156

Several agents that inhibit IL-15 activity have been developed, including soluble IL-15Rα, mutant IL-15 molecules, and antibodies specific for IL-2/IL-15Rβ. For example, in vivo, the IL-15 mutant markedly diminished antigen-specific delayed-type hypersensitivity responses in Balb/c mice and increased survival of pancreatic islet cell allografts. The use of soluble high-affinity IL-15Rα inhibited the development of mouse collagen-induced arthritis and inhibited allograft rejection. An antibody specific for IL-15 has been efficacious in mouse models of psoriasis. This antibody is now in a phase I/II clinical trial in patients with rheumathoid arthritis. Finally, a humanized antibody specific  for IL-2/IL-15Rβ when administered as a single agent prolonged cardiac-allograft survival in cynomolgus monkeys, and only minimal toxicity was noted when this antibody was given in a phase I trial to patients with T cell large granular lymphocytic leukemia.

Basic components of the immune system part 155

It is believed that IL-15 might contribute to autoimmune diseases by inducing the expression of TNF-α,  by inhibiting self-tolerance mediated by IL-2-induced AICD, and by facilitating the maintenance of CD8 memory T cell survival, including that of self-reactive memory cells. For example, dysregulated  IL-15 expression has been reported in patients with a range of autoimmune diseases such as multiple sclerosis, inflammatory bowel disease and psoriasis. In this context, cytokine-directed blockade of TNF with specific monoclonal antibodies or soluble TNF receptors has been an important target for many of the diseases mention previously. Yet TNF-directed therapies do not provide effective therapy for all these patients, and new theurapeutic targets are needed. Furthermore, although TNF-directed therapy has an anti-inflammatory effect, it does not have an effect on self-reactrive memory T cells that might play a role in the pathogenesis  and maintenance of autoimmune diseases. Thus, it is hoped that by targeting IL-15 it might be possible to both achieve the anti-inflammatory effects and reduce the number of CD8 self-reactive memort T cells.

Basic components of the immune system part 154

The unique IL-2 and IL-2Rα system has been a valuable target for immunotherapy because  IL-2Rα is not expressed by any resting cells with the exception  of T regulatory cells. Yet, it is expressed by many malignant cells of various T- and B-cell leukemias, T cells that participate in organ allograft  rejection, and finally by T cells involved in autoimmune ease. Thus, antibodies directed against  IL-2Rα (several such antibodies have been aproved by FDA for use in humans) specifically destroy those cells that are IL-2 dependent. One of these antibodies (daclizumab by Hoffmann-La Roche) is in phase II trials in patients with uveitis, in certain multiple sclerosis patient, and in asthma patients. Finally, it was shown to be effective in a subset of patients with adult T-cell leukemia due to human T-cell lymphotropic virus 1.

Basic components of the immune system part 153

In contrast, mice that are deficient in IL-15, or its receptor IL-15Rα, do not develop enlarged lymphoid tissues, increased serum immunoglobulin, or autoimmune disease. Rather they have a marked reduction in the number of thymic and peripheral natural killer (NK) cells, NK T cells, and intestinal intraepithelial lymphocytes. Thus, IL-15Rα-deficient mice show a marked reduction in CD8CD44  memory T cells. The differences of the function of IL-2 and IL-15 reflect the distinct modes of actions of these two cytokines. IL-2 functions as a secreted cytokine, acting on preformed heterotrimeric receptors expressed on activated T and NK cells. In contrast, IL-15 and IL-15Rα expressed on the surface of antigen-presenting cells are presented in trans to CD8 T cells and NK cells that express only the β and γ chain of the IL-15 receptor.

Basic components of the immune system part 152

These observation from ex vivo functional studies are supported by studies in mice defficient in cytokine or cytokine receptor genes. For example, IL-2 deficient and IL-2Rα-deficient mice develop a marked enlargement of the peripheral lymphoid organs and polyclonal expansion of T and B cells, and this proliferation reflects the impairment of regulatory T cells and AICD. These mice develop autoimmune diseases such as hemolytic anemia and inflammatory bowel  disease.

Basic components of the immune system part 151

There are several distinct differences in the functions of IL-2 and IL-15. IL-2 is involved in checkpoints or brakes on the immune system. IL-2 is required to maintain the competitiveness of forkhead box P3- (FoxP3-) expressing regulatory T cells, and plays a crucial role in activation-induced cell death (AICD), a process that leads to the elimination of self-reactive T cells. Thus, the unique feature of IL-2 is to prevent T cell immune response to self that would lead autoimmunity.  In contrast, IL-15 expression has no effect on regulatory T cells  but is an anti-apoptotic factor in several systems. Furthermore,  IL-15 promotes the maintenance  of CD8+ CD44 memory T cells. Thus, IL-15 has its primary role the maintenance of a robust memory response to invading pathogens.

Basic components of the immune system part 150

The common cytokine receptor γ chain is used by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. The IL-2R and IL-15R have a second (β chain) subunit  in common as well, but have unique α subunits. These two cytokine receptors use a common signaling pathway that involves JAK1, JAK3 and STAT5. The signaling involves the phosphorylation of STAT5 that results in the dissociation of STAT5 from the receptor and the subsequent dimerization of STAT5. The dimers then translocate to the nucleus and promote transcription of target genes.

Basic components of the immune system part 149

CYTOKINE IMMUNOMODULATION

Although many of the immunoregulation techniques revolve around the humoral arm of the immune response, there is increasing interest in targeting T cells or the cytokines regulators to regulate the elimination of autoreactive  T cells, tumour cells, and the maintenance of a specific memory response to these pathogens. Such immmune responses are normally  regulated by cytokines, and the activities of the cytokines have a high degree of redundancy

Basic components of the immune system part 148

HPV infection is usually sexually acquired, and it is estimated that currently 20 million people  are infected in the United States. The infection has no real signs or symptoms, and HPV may lead to cervical cancer. It is estimated that ten of the thirty different serotypes of the virus can induce cervical cancer, so the vaccine has been directed at eliminating those serotypes. Thus, if 10,000 women are infected with one of the high-risk viral serotypes, approximately 3,900 of them will die of cervical cancer. The new vaccine, if given before active sexual activity in women, can prevent the viral infection and thereby markedly diminish  the risk of cervical cancer. Because of the possible success of this vaccine, it may be worthwhile to look at how to prevent the Epstein-Bar virus in at-risk children to prevent or diminish the risk of Burkett's lymphoma in children infected with the virus.

Basic components of the immune system part 147

Although we have mainly been discussing various forms of vaccination to protect against the invading organism, one of the most interesting new vaccines has not been developed to eliminate the infectious agent but rather to prevent the development of another far more serious disease - a complication of the initial infection. This is the Gardisal vaccine manufactered by Merck to protect against human papilloma virus (HPV).

Basic components of the immune system part 146

The immunological response to the killed organism or product thereof has been enhanced by  the use of adjuvants. Although the most common adjuvant for animal studies has been the complete Freund's adjuvant, it cannot be used in humans because it causes liver, skin and spleen dysfunction. The most common adjuvant for humans is aluminium compounds, which are generally safe for human use. Others include muramyl dipeptide, biodegradable polymers, and a glycoside adjuvant called Quil A from the bark of an Amazon oak tree. However, many others are being developed or will probably be given U.S Food and  Drug Administration (FDA) acceptance in the future. The key feature will be their immunogenic enhancement and their strength of safety for use in humans.

Basic components of the immune system part 145

Killed  vaccines consist of suspensions of killed organisms such as typhoid, cholera, and pertussis (although there is now an acellular vaccine) or one of the products or fractions of the organisms. These include toxoids of diphtheria and tetanus and subunits of viruses such as surface hepatitis B antigen. Among the most  successful of these types of vaccines has been the use of polysaccharides in the pneumococcal, meningococcal and haemophilus influenza vaccines. In general, the killed vaccines are not as effective as the live viruses because they do not give long-lasting immunity as a live infection does. For example, although the tetanus toxoid vaccine is effective, it requires a booster dose every ten years.

Basic components of the immune system part 144

Live attenuated vaccines are useful because they infect, replicate, and immunize in a manner similar to natural infection but with milder clinical symptoms. Examples include many of the childhood infections such as measles, mumps, and rubella (MMR vaccine), chicken pox (varicella) and Bacille Calmette-Guerin (BCG) for tuberculosis. Although millions of doses have been administered with no complications, if given to an immunocompromised  host (such as primary immunodeficiency or secondary to HIV infection), these live vaccines may cause serious disease.

Basic components of the immune system part 143

IMMUNITY

The two ways to achieve immunity are actively and passively. Active immunity is achieved  when exposure to a foreign stimulus triggers an immunological  response to the agent by the host. The best immunity to an agent   is achieved by natural infection, which evolves  with a clinical or subclinical  response to the agent by the host. Artificial active immunization is the administration of an immunogen as a vaccine. Vaccines may be live organisms, killed organisms, or modified toxins. Although no vaccine is ideal and each has its problems, the problems of live vaccines are generally related to their safety, while the problems of killed vaccines are related mainly to their effectiveness.

Basic components of the immune system part 142

Immunization

Prevention of infectious diseases depends on many factors. Foremost is the presence of a clean water supply, development of sanitary facilities, good nutrition, and good personal hygiene. More recently, immunization against a particular agent has been the most effective measure in controlling infectious disease. Yet, with the emergence of new infectious agents such as hepatitis C and HIV, novel approaches will be needed to generate new and effective vaccines.

Basic components of the immune system part 141

Adoptive Immunotherapy

Adoptive immunotherapies involve the transfer of either cells or antibodies into a host. These are also referred to as passive therapies, since the host does not actively mount its own  immune response. Examples include infusion of hepatitis B immune globulin and the adoptive transfer of antigen-specific T lymphocytes to treat a chronic viral infection or cancer.

Basic components of the immune system part 140

IL-2 is produced by stimulated CD4 T cells  and induces clonal expansion of IL-2 T and B cells  is used in immunodeficiency states such as HIV infection where IL-2 production is defective. In patients with HIV infection and baseline counts of CD4 above 200ml, intermitten IL-2 infusions have been shown  to produce substantial and sustained increases in CD4 counts. IL-2 has side effects similar to IFN-α, with most of the effects being flu-like. The most serious  side effect is IL-2 action on IL-1, IFN-γ and TNF, all mediators of vascular permeability, resulting in marked hypotension, pulmonary edema and neuropsychiatric symptoms.

Basic components of the immune system part 139

IFN-γ is a potential activator of macrophages and is most often used in conditions in which defective macrophage function  occurs. Examples of these disorders are lepromatous leprosy, leishmaniasis and chronic granulomatous disease. IFN-γ works by increasing phagocytic bactericidal activity, but only some patients show enhanced superoxide activity, implying that  IFN-γ works by several different mechanisms.

Basic components of the immune system part 138

IFN-β has been shown to be of benefit in patients with relapsing-remitting multiple sclerosis, and IFN-β1 appears to decrease the rate of progression of disability. Despite these results, the precise therapeutic role of IFN-β is still controversial.

Basic components of the immune system part 137

CYTOKINE THERAPY

Interferons are antiviral glycoproteins, which are secreted  as a result of a viral infection and have wide-ranging antitumor and immunomodulatory effects. They have attracted much interest as immunotherapeutic agents. Interferons bind to cell surface receptors and activate secondary intracellular changes which inhibit viral replication. They can be divided into three groups: alpha (α), beta (β) and gamma (γ) interferons. All three interferons have been genetically enginered, and recombinant IFB-α,-β, and -γ are available, but IFN-α is the best studied. IFN-α is the treatment of choice for hepatitis B and C; when given systemically, it produces significant clearing of hepatitis B in chronic carriers. IFN-α has some side effects, mainly flu-like symptoms such as fever, malaise, and anorexia- all symptoms that can be tolerated. More severe effects are reversible: bone marrow depression, liver dysfunction and cardiotoxicity.

Basic components of the immune system part 136

IMMUNOPOTENTIATION

Chronic infection such as HIV and hepatitis C are characterized by an inability of the host to control viral replication. The ability to potentiate the host immune response to control to control chronic infections is an important goal and is under active investigation. It has also been shown that at least some types of cancer can be controlled by the host immune system, so potentiation of the host immune system may prove useful in treating these cancers. There are three principal ways to potentiate the immune response in humans through cytokines, adoptive immunotherapy or vaccination

Basic components of the immune system part 135

Total lymphoid irradiation produces long-term suppression of helper T-cells and has been used in some severe autoimmune diseases like lupus or rheumathoid arthritis. The side effects of this treatment may be severe and sometimes fatal.

Basic components of the immune system part 134

Other method of immunosuppressions are plasmapheresis or plasma exchange. In the first method, improvement may be due to removal of mediators of tissue damage, whereas in plasma exchange, it may be due to replacement of deficient factors or to the immunomodulatory effects of human immunoglobulins.

Basic components of the immune system part 133

Some new studies, still in clinical trials, are occuring in the treatment of prostate cancer, especially metastatic bone lesions, and it is hoped many more monoclonal antibodies will be forthcoming against various other tissues.

Basic components of the immune system part 132

Monoclonal antibodies can also be used as antitumor agents. Specific targeting and killing of tumour cells can be enhanced by linking tumor-antigen specific monoclonal antibodies to agents as follows:

• A cytotoxic drugs such as methotrexate
• A radioisotope such as iodine-131 or ytrium-90
• A toxin such as ricin

Monoclonal antibodies are now approved for the treatment of non-Hodgkin's lymphoma, myeloid and lymphocytic leukemia, breast cancer and colorectal cancer.

Basic components of the immune system part 131

More recently, monoclonal antibodies are being used to suppress the immune system, and several antibodies are now approved for the treatment of autoimmune diseases. These antibodies are typically "humanized" mouse monoclonal , created by transposing the mouse antigen-binding sites onto a human antibody framework. This technique retains the full range of effective properties of human Fc while minimizing  the immunogenicity of the mouse component. Antibodies that target the immune system can target cell surface molecules on T or B cells or can target soluble mediators of inflammation such as cytokines. Among the most effective uses of monoclonal antibodies has been in treating severe rheumathoid arthritis, using monoclonal antibody directed against tumor necrosis factor (TNF-α). The drawback to this therapy is that the infusion must be repeated frequently to sustain results.

Basic components of the immune system part 130

ANTIBODIES AND OTHER IMMUNOSUPPRESSIVE METHODS

There are a number of instances in which antibodies  have been used to suppress the immune response. Among the earliest measures has been the use of anti-RHD antibodies to prevent hemolytic disease of the newborn due to incompatibility between the mother (RHD-) and RHD+ fetus. The disease is prevented by the administration of anti-D antibodies to the mother immediately after delivery. This inhibits the formation of anti-D antibodies in the mother, thereby avoiding the development of serious disease in infant. This therapeutic measure has virtually eliminated the incidence of RH disease in developed countries.

Basic components of the immune system part 129

Cyclosporin,  a naturally occuring fungal metabolite, also inhibits T-cell activation and cell-mediated immunity. The drug becomes active only when complexed  to its intracellular receptor  cyclophilin, and it inhibits  early calcium-dependent events, especially the activation of several cytokine gene. Its major effect is the inhibition of IL-2 production and the CD4 proliferation responses. Cyclosporin has been extremely useful in the control of transplant rejection and is also used in several autoimmune diseases such as psoriasis and severe rheumathoid arthritis. However, long-term use has demonstrated severe toxicity such as nephrotoxicity and hepatotoxicity and particularly lymphoma induction.

Basic components of the immune system part 128

Another group is the alkylating agents, of which cyclophosphamide is one of the best examples. This drug also requires activation by the liver. It inhibits cell division  and can suppress antibody production, and it decreases delayed-type hypersensitivity. Methotrexate, which inhibits cell division by disrupting folic acid metabolism, has similar immunomodulatory effects.

Basic components of the immune system part 127

The development of the thiopurines in the 1950s ushered in a new group of immunosuppresive agents, the most important of them being azathioprine. It is inactive until it is metabolized in the liver and takes three to four weeks to be effective. The metabolites work by inhibiting  DNA synthesis in dividing cells (such as activated lymphocytes). Like many other drugs, it has side effects, mainly in bone marrow toxicity, and long-term use eventually results in granulocytopenia and thrombocytopenia.

Basic components of the immune system part 126

The side effects of steroids are numerous and often depend on both the dose used and duration of treatment. These include an increased susceptibility to infection, osteoporosis, and growth disturbances in children, as well as gastric ulcers, hypertension, acne, and hirsutism. By giving larger doses for shorter periods, many of these side effects are lessened.

Basic components of the immune system part 125

In humans, steroids are used for two main purposes. One is prevention  or reversal of graft rejection. The other is in the treatment of autoimmune and malignant diseases. Corticosteroids modulate inflammation by suppressing cytokine- and chemokine- encoding genes, which inhibits the activation and recruitment of inflammatory cells.

Basic components of the immune system part 124

IMMUNOSUPPRESSION

Immunosuppresive drugs

Several groups of drugs suppress the immune system. Among the oldest of these drugs are the corticisteroids, which have long been  known to alter immune responses. When corticosteroids are given, the result is  a transient  lymphophenia peaking at four hours and lasting up to twenty-four hours. Helper T cells are predominantly affected, and at higher doses of steroids inhibition of interleukin-2 (IL-2) production by helper T cells becomes increasing important. Another major effect in humans is on resting macrophages (activated macrophages are not sensitive)

Basic components of the immune system part 123

IMMUNE REGULATION

The immune system in general responds appropriately to the presence of foreign antigens. However, there are certain diseases that arise from either a defective or over-responsive immune system on the part of the host. Two major therapeutic approaches are possible: either immunosuppression or immunopotentiation of the immune system.

Basic components of the immune system part 122

The use of microarray assays has grown in the past decade and will continue to grow. The use of these assays has a role in diseases associated with human genetics and provides information on which cytokines or lymphokines are important in disease states.

Basic components of the immune system part 121

FUTURE DIRECTIONS IN RESEARCH

The use of monoclonal antibodies, especially "humanized" ones, will play an increasingly important role in both basic immunology and clinical immunology. Their use will be in both detection of small and early tumours and in the treatment of tumors. The success of monoclonal antibodies in metastatic prostate cancer is already well established. It is believed that other tumour therapies will follow in the future.

Basic components of the immune system part 120

The method is relatively straightforward. One takes the tissues or cells to be studied and prepares them as follows;

Tissue-->mRNA-->cDNA-->Biotinylated cRNA

The bioinylated material is layered on glasss slides on which DNA fragments of the human genome have been placed (12.000 probe sets/clip). The chips are then washed, stained with streptavidin-phycoerythrin, and scanned with a probe array scanner.